1. Academic Validation
  2. Systematic Assessment of Fragment Identification for Multitarget Drug Design

Systematic Assessment of Fragment Identification for Multitarget Drug Design

  • ChemMedChem. 2021 Apr 8;16(7):1088-1092. doi: 10.1002/cmdc.202000858.
Steffen Brunst 1 Jan S Kramer 1 Whitney Kilu 1 Jan Heering 2 Julius Pollinger 1 Kerstin Hiesinger 1 Sven George 1 Dieter Steinhilber 1 2 Daniel Merk 1 Ewgenij Proschak 1 2
Affiliations

Affiliations

  • 1 Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue Str. 9, 60438, Frankfurt, Germany.
  • 2 Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Theodor-Stern-Kai 7, 60596, Frankfurt, Germany.
Abstract

Designed multitarget ligands are a popular approach to generating efficient and safe drugs, and fragment-based strategies have been postulated as a versatile avenue to discover multitarget ligand leads. To systematically probe the potential of fragment-based multiple ligand discovery, we have employed a large fragment library for comprehensive screening on five targets chosen from proteins for which multitarget ligands have been successfully developed previously (soluble Epoxide Hydrolase, leukotriene A4 hydrolase, 5-lipoxygenase, retinoid X receptor, farnesoid X receptor). Differential scanning fluorimetry served as primary screening method before fragments hitting at least two targets were validated in orthogonal assays. Thereby, we obtained valuable fragment leads with dual-target engagement for six out of ten target combinations. Our results demonstrate the applicability of fragment-based approaches to identify starting points for polypharmacological compound development with certain limitations.

Keywords

differential scanning fluorimetry; fragment-based drug design; multitarget drugs; polypharmacology.

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